ABSTRACT - PROJECT 3 Allogeneic hematopoietic cell transplantation (HCT) provides graft-vs-tumor (GVT) reactions that may cure patients with advanced lymphoma. We developed a well tolerated, reduced intensity conditioning regimen with low-dose total body irradiation (TBI) (2 Gy) with fludarabine (FLU; 30 mg/m2 3) that provides reliable engraftment for allogeneic HCT from HLA-matched related or unrelated donors. This regimen allows treatment of older patients nearer the median age of presentation for these diseases or those with comorbidities unable to tolerate myeloablative HCT. Most anti-tumor activity is from GVT responses that develop as post-grafting immunosuppression is withdrawn. Nearly 90% of the causes of HCT failure are relapse and graft-vs.-host disease (GVHD) related nonrelapse mortality (NRM). Relapse risk depends on tumor histology and tumor bulk at the time of HCT with the highest risk of relapse in patients with bulky disease, aggressive NHL not in remission, and HL patients who have failed prior autologous HCT. Better treatments are needed to reduce and control disease until GVT effects emerge. Increasing the intensity of nonspecific, systemic conditioning by increasing TBI or chemotherapy in this population has been poorly tolerated and increases NRM. Radioimmunotherapy (RIT) using anti-CD20 monoclonal antibodies (mAb) conjugated with iodine-131 (131I; gamma and beta-emitter) and yttrium-90 (90Y; beta-emitter) combined with our FLU/TBI conditioning regimen has been shown to be safe; however, the long path-length, long half-life, and relatively low-energy of these radioisotopes may not provide enough targeted radiation, and may be blocked by circulating levels of rituximab from prior therapy. We propose to augment transplant conditioning with anti-CD45 mAb coupled to the alpha- emitting radionuclide astatine-211 (211At). The short path length of the alpha-emitter, high energy, and short half-life may reduce both early toxicities and late effects, such as secondary cancers, associated with conventional beta-emitter RIT. We hypothesize that alpha particle anti-CD45 RIT may provide additional anti- tumor activity, as well as lower the barriers to engraftment without greatly increasing NRM for the treatment of both B and T-cell NHL and HL at a high risk of relapse using FLU/TBI alone. Accordingly, Specific Aim 1 will evaluate 211At anti-CD45 mAb in combination with reduced intensity allogeneic HCT from HLA-matched related and unrelated donors. In order to extend the option of HCT to patients without HLA-matched donors and better serve patients from minority groups, we have developed a reduced intensity regimen using HLA-haploidentical donors. While the regimen is well tolerated with a low rate of GVHD, relapse and immunodeficiency remain high, likely due to the post HCT immunosuppression with cyclophosphamide to control GVHD. Specific Aim 2 will address this using adoptive immunotherapy with donor NK cells and with infusions of gene modified donor T lymphocytes expressing an inducible iCaspase-9 gene that can be ablated with a dimerizing agent in the advent of severe GVHD. We hypothesize that this will reduce relapse and immunodeficiency post HCT.